Adenosine (9-.beta.-D-ribofuranosyl-9H-purin-6-amine) was characterized in the late 1920's as having hypotensive and bradycardic activity. Since then, considerable research in the molecular modification of adenosine has led to the general conclusion that cardiovascular activity is limited to analogs having intact purine and .beta.-ribofuranosyl rings.
Further research more clearly defined how the activity of these adenosine analogs affected the purinergic receptors in peripheral cell membranes, particularly the A.sub.1 and A.sub.2 receptors.
Adenosine antagonists have helped explain the role of adenosine in various physiological processes. Specifically, selective antagonists for the adenosine A.sub.1 receptor were critical in defining the physiological importance of A.sub.1 receptor activation. Non-selective adenosine antagonists such as caffeine and theophylline served as starting points for structure activity research with the goal of creating A.sub.1 receptor selective antagonists. An example of such a discovery is 8-(Dicyclopropylmethyl)-1,3-dipropylxanthine (Shimada, J., et al., J. Med. Chem., 34:466-9 (1991)). Alternatively, various non-xanthine adenosine antagonists have been identified, including triazolo[4,3-a]quinoxalinamines, triazoloquinazolines, pyrazolo[4,3-d]pyrimidin-7-ones, and adenine derivatives (Williams, M., Med. Res. Rev., 9(2):219-43 (1989)). A series of adenine derivatives was identified in U.S. Pat. No. 5,066,655. The search continues for potent and selective adenosine A.sub.1 receptor selective antagonists, useful as pharmacological tools and as therapeutic agents.